Dasotraline for ADHD

Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetra-hydronaphthalene-1-amine] is a dopamine and norepinephrine reuptake inhibitor with weak serotonin reuptake inhibition:¹

• DAT: IC50 = 3 nM
• NET: IC50 = 4 nM
• SERT: IC50 = 15 nM

Tetrodotoxin blocked neuronal firing and abolished the ability of dasotralin to increase synaptic monoamine concentrations, demonstrating that dasotralin is a reuptake inhibitor and not a monoamine releaser.¹

Dasotraline has been studied in relation to its use in ADHD ²³
Sunuvion is said to have discontinued development of dasotralin in the meantime.⁴

Orally ingested dasotraline is slowly absorbed in humans, with a tmax of 10-12 hours and a very long terminal elimination half-life of 47-77 hours.¹ Dasotraline may have a sustained treatment benefit in ADHD due to its stable plasma concentration over 24 hours when administered once daily while having a low potential for abuse.⁵ Dasotraline thus differs markedly from the rapid, large, and short-lived increase in dopamine efflux of d-amphetamine and MPH.

In a placebo-controlled double-blind study, a single daily dose of 8 mg dasotraline (but not 4 mg dasotraline) showed significant improvement in ADHD-HI Rating Scale (ADHD-HI) symptoms and CGI-S scores at 4 weeks compared with placebo.⁶

At 4 mg, a good 10% of subjects terminated the study prematurely, at 8 mg just under 28%. This appears to be quite high.
The high insomnia could result from the long half-life of 47 hours, which, on the other hand, would allow a single daily dose leading to a constant plasma level after 10 days of ingestion.⁷⁸
On the other hand, insomnia was not a predictor of dropout from study participation.

Another 6-week RCT of 342 children aged 6-12 years found significantly better improvement in ADHD symptoms with 4 mg/day than placebo, with an effect size of 0.48. 2 mg/day showed no improvement⁹
Discontinuation rates due to adverse events were 12.2% (4 mg/day), 6.3% (2 mg/day), and 1.7% (placebo), respectively.

Side effects in the studies were mainly (compared to placebo):

• Sleep problems
  • These are likely to result from the long half-life
• Dry mouth
• Nausea
• Postural orthostatic tachycardia syndrome (5.4% vs. 0%)
• Perceptual disorders (5.4% vs. 0%)
• Decreased appetite (10.7% vs. 3.6%)
• Weight loss
• Irritability (5.4% vs. 3.6%)
• Headache (10.7% vs. 8.9%)
• Affect lability (8.9% vs. 7.1%)

A study in adults with 6 mg/day found only partially significant improvements in ADHD symptomatology over placebo, but a trend toward improvement. This was due to a surprisingly large improvement in the placebo group ¹⁰¹¹

No serious side effects or clinically relevant changes in blood pressure or heart rate were found.